SOP on Technology Transfer of Drug Product

Technology transfer/product transfer is a complete documented process that covers the detailed documentation for manufacturing and dispatch of the first batch, received from the parent location or FDD of a new or existing product from a particular site with manufacturing, packaging and analytical details.

SOP on Technology Transfer of Drug Product

1.0      PURPOSE:

  • The purpose of this SOP is to define the procedure to be followed for a successful transfer of new technology or product (Technology Transfer of Drug Product) from-
    • One manufacturing site to another site of same manufacturing group / company or
    • Formulation Development Department (FDD) / R&D to manufacturing site.

2.0      SCOPE :

  • Scope of this SOP covers
    • All existing products being transferred from one site to another site and
    • New products from FDD .

3.0      REFERENCES:

  • SOP for Risk Management
  • SOP for Stability Program
  • Analytical Method Transfer procedure
  • WHO Guidance on Tech Transfer
  • Change Control Procedure

4.0      RESPONSIBILITY:

  •  Formulation Development (FDD):-
    • Responsible to provide Technology transfer documents (MPS/PIF) to location.
    • Organize meeting with location after circulation of above documents,
    • if required, Present at location while manufacturing of initial batches.
    • Specification,
    • Analytical Test Procedure,
    • Analytical Method Validation and
    • Organize meeting with location after circulation of above documents, and
    • if required, Guide /support and demonstrate about the skill involved in analysis as per requirement.
    • Approved art works,
    • Packaging material descriptions
    • Pack profile to location
    • Participate new product launch meeting and process development/scale up trials if required.
  • Production Officer / Executive:-
    • Responsible for review of-
    • Product Information File (PIF) / Master Product Specification (MPS) on receipt,
    • Plan for batch,
    • Raise Purchase Request (PR) for additional facility required,
    • Up-load the Bill of Material (BOM) in Metis or other adopted software and
    • Prepare of Batch Manufacturing Records (BMR) / Batch Packing Record (BPR), Risk Assessment Report (FMEA).
  • Warehouse Dept.:-
    • Responsible to Raise Purchase Request for Raw materials / Packing materials, check availability of materials.
    • Ensure that materials are receipt & stored as per SOP of receipt.
    • Storage of materials.
    • Dispensing of material as per the batch manufacturing plan.
    • Review of the PIF/MPS on receipt, authorize, issue the BMR / BPR, plan validation activity as per validation plan,
    • Review Risk Assessment Report / FMEA report and evaluate mitigation plan prior to the manufacturing of batches.
    • Preparation of Standard Testing Procedure (STP), Analytical Test Data Sheet and
    • Qualification of working standards in accordance with the product requirements.

5.0      DEFINITION:

  •  Technology Transfer:
    • Technology transfer/product transfer is a complete documented process which covers the detailed documentation for manufacturing and dispatch of first batch, received from the parent location or FDD of a new or existing product from a particular site with manufacturing, packaging and analytical details.
  • Master Product Specification (MPS):
    • The MPS most importantly have below information but not limited to the following,
    • ERP code for, Active pharmaceuticals ingredient (API), Excipients and Primary packing material/s.
    • Drug substance, excipients & primary packaging material sourcing.
    • Detailed Manufacturing formula along with bill of materials (BOM).
    • Precautions / Handling / Storage / Sampling details where ever required.
    • Brief manufacturing process.
    • Critical equipment list/critical process requirements.
    • Required utility/consumable list.
    • Information regarding tooling / change parts (size, shape, diagram /drawing).
    • Primary packing material specifications.
    • In-process specification and finished product specification.
    • Stability data and MSDS (API / Excipient / Finished product), Draft Label and Flow chart.

6.0       PROCEDURE FOR TECHNOLOGY TRANSFER:

  • Technology Transfer of New Product/ Transferred Product (Domestic):
    • FDD/ADD or Transferring location/Site transfer all the documents related to technology transfer of new batch/ transferred batch to the site.
    • Intimate the site QA for any additional document required and ensure the availability of the same.
    • After receiving the documents from the FDD/ADD or transferring location/site, QA officer make the necessary entries in the checklist for new / transferred product (Annexure 1) and
    • Issue it to all involved departments for checking of documents related to their concerned area.
    • All involved department check the technology transfer document and fill the checklist (Annexure-1) and returned it to the QA department.
    • QA executive / officer can also fill the check list for new product transfer in consultation with the concerned department heads.
    • QA executive / officer review the readiness / availability of documents.
    • Intimate for required precaution / measures in analytical method to site QC from ADD.
    • Ware house raise the purchase order for the raw material and packaging materials.
    • Tablets size,
    • Shape,
    • Quantity and
    • Type of tooling (B or D) for available tablet press.
    • Mention special precautions/features required for tooling in MPS if specified by FDD.
    • For example, lower punch with key and hard chrome platting on punches.
    • Production department / PDD order the capsules change parts as per the size and requirement by FDD along with MPS.
    • Packing department / PDD order the packing change parts as per the size and requirement by FDD along with MPS.
    • Once all raw materials, packing materials, change part, tooling and FDA permission for the product are received, FDD be informed for support to establish the manufacturing parameters.
    • Manufacturing BOM, MBMR, packing BOM, MBPR, Spec./ ATP of all respective products to be prepared prior to the manufacturing plan.
    • Make sure the availability of Raw material and packing material prior to the manufacturing plan.
    • Prior to the manufacturing of first batch (Issuance of BMR for first batch) of the product on site,
    • If required, first batch of new / transferred product manufactured in presence of FDD / transferring site Production personnel,
    • Therefore to know about the critical or key step as well as a precaution needed to be taken while manufacturing commercial batches.
    • Based upon the first three batches, Hence in case of any changes to be incorporated, FDD  revise the MPS and accordingly the MBMR / MBPR   prepared.
    • The stability sample is withdrawn by IPQA & perform stability study as per SOP of “Stability Program”.
    • For first three batches, an “Inspection report” most importantly  filled by packing officer and cross verified by IPQA officer.
    • Minimum 5 packed shippers checked for first three batches during its packaging.
    • After completion of packing process (during closure of BPR),Finally the batch release authorization for New Product filled by QA prior to the release of batches (For 1st three commercial batches).

6.0       ABBREVIATIONS:

  •  ADD : Analytical Development Department
  • API : Active Pharmaceutical Ingredient
  • BMR : Batch Manufacturing Record
  • BPR : Batch Packing Record
  • BOM : Bill of material
  • COA : Certificate of Analysis
  • CQ : Corporate Quality
  • ERP : Enterprise resources planning
  • FDA : Food and Drug Administration
  • FDD : Formulation Development Department
  • FMEA : Failure Mode Effect Analysis
  • LIMS : Laboratory Information Management System
  • MF : Master Formula
  • MFC : Master Formula Card
  • MPS : Master Product Specification
  • MSDS : Material Safety Data Sheet
  • PDD : Packaging Development Department
  • PIF : Project Information Form
  • PR : Purchase Requisition
  • QA : Quality Assurance
  • QC : Quality Control
  • R & D : Research and Development
  • RS : Reference Standard
  • SOP : Standard Operating Procedure
  • STP : Standard Test Procedure
  • WRS : Working Reference Standard

7.0      ANNEXURES

Annexure – 1

Checklist 1 of 3
Checklist 3 of 3

Annexure – 2

New Product Manufacturing Authorization

ProductDosage form
API Used

FOR COMMERCIAL PRODUCT

Sr. No.RequirementsAvailable Yes/ NoEnsured By (QA)Comments/ Commitments
1D.C.G.I. permission (If Applicable)
2F.D.A. Manufacturing License
3Excise formalities (if any).
4Raw material specification
5Packing material specifications
6Finish Product specification
7Batch manufacturing  record
8Batch Packing record
9Raw materials availability
10Packing materials availability
11Data on material safety, excipients handling or any critical controls for environment, storage and product (If any)
12Availability of accessories and machinery parts for manufacturing as well as packaging (punches, spares, etc.)       
13Analytical method
14Reagents, reference standards, working standards and impurity standards
15Process Validation Protocol, sampling  tools.
16Any other special requirement (……………………………………………)
17Any other special requirement (……………………………………………)

Based on the available data, we hereby authorize the product to be released for manufacturing subject to above criteria being satisfied.

DepartmentCommentsSign & Date
Warehouse Head
Manufacturing Head
Packing Head
QC Head
Engineering Head
EHS Head
Regulatory Affairs
Production Head
QA Head
Head Quality
Plant Head

Annexure – 3

New Product Packing Inspection Report

Technology Transfer of New Product

SOP on Operation of Colloid Mill

The purpose of this standard Operating Procedure (SOP) is to lay down a procedure for operation of colloid mill.

This procedure is applicable to operation of colloid mill at manufacturing facility of Pharmaceutical Industry.

  • PROCEDURE:
    • Ensure that area is cleaned as per SOP.
    • Ensure that all the parts of colloid mill are cleaned as per SOP.
    • Ensure mains are ‘OFF’ and plug top is removed from socket.
    • Diagram:
  • Check that screws on rotor (3 in No.) are properly fitted.
    • Rotate the rotor by hand and ensure free movement.
    • Place the outer ring and turn it clockwise to match scale with indicator mark (scale to be set as per product requirement).
    • Tighten the handles on the sides so that ring is locked in position.
    • Place the neoprene food grade gaskets followed by top ring and hopper.
    • Tighten the bolts of hopper.
    • Put ‘ON’ the mains and check direction of rotation (direction of rotation should be long the arrow marked on the body of the machine).
    • Fix the recirculation/outlets nozzle along with gasket.
    • Take the line clearance as per SOP and record the line clearance activity in Annexure.
    • Take a trial with purified water.
    • Ensure absence of leakage or abnormal noise. Affix ‘USE FOR’ label on machine with product name, date and sign of production officer.
    • Feed the solution/suspension to be milled in hopper and switch ‘ON’ the Colloid mill.
    • Mill the solution/suspension in single pass or multiple pass (recirculation) by adjusting the knob   on the outlet nozzle (as per product requirement). Check the grittiness of out coming suspension.
    • Rinse the colloid mill with solvent/purified water.
    • Switch ‘OFF’ the colloid mill.
    • Affix ‘TO BE CLEANED’ label on the hopper with Equipment no., previous product, Batch No., Date, and Signature of production officer.
    • Record cleaning activity as per SOP in Cleaning and Usage Log of Equipment and Area.
    • Calibration :
      • RPM of colloid mill every 12 months by outside party.
      • Frequency every 12 months.

NOTE:      1.    Colloid Mill Should Be Cleaned Immediately After Use.

                   2.    Set The Colloid Mill At ‘0’.

                   3.   If Colloid Mill produces any abnormal noise should be reported to

                         Engineering department immediately.

                   4.   Never live machine with material overnight.

                  5.   Check the direction of rotation of the rotor before starting of the

                         machine. ‘Direction of rotation of the mill must be clockwise’.

  • TRAINING:

As per Employee training SOP

  • DISTRIBUTION:

As per SOP for SOP

  • ANNEXURE:

Nil.

SOP for Handling Punches and Dies

The purpose of this standard Operating Procedure (SOP) is to lay down a procedure for handling and control of punches and dies, used during compression.

This procedure is applicable for procurement, usage, cleaning, maintenance and disposal of all the punch sets (i.e. new and in use) and related testing kits, i.e. punch height checking kit and punch polishing kit used in Tablet department at manufacturing facility of Pharmaceutical Industry.

  • PROCEDURE:
    • ORDERING NEW PUNCHES AND DIES:
      • ORDERING OF NEW SET OF PUNCHES AND DIES OR ORDERING OF EXISTING PUNCH SET WITH NEW PARTY.
        • Drawing’ for Upper punch, Lower punch and Die should be prepared by the manufacturer as per the specifications given or as per sample punch set. 
        • After primary approval of the drawing, sample punch set (1Upper punch, 1 lower punch and 1 die) will be received from the supplier.
        • Department Head will approve ‘Sample punch set’ after taking a trial on the machine.
        • Standard specification of punch set for respective product is prepared after successful trial and approval of sample  write down in appropriate Annexure.
        • After approval of the ‘Sample punch set’, Purchase order for the full set of punches and dies will be initiated by the Purchase Department Head, and authorized by the Unit Head, giving following details:-
          • The total number of punches and dies required for Compression machine will be as follows.
          • Example :-  For 26 station m/c: 31 sets, For 32 station m/c: 37 sets, For 55 station m/c: 60 sets
          • Type of Tooling required e.g. D/B type.
          • Material of construction to be used (High Carbon High Chromium (HCHC) /Oil Hardened Not Shrinkable (OHNS)).
          • Engraving/laser etching of following details on individual punch
            • Serial number.
            • Name of the manufacturer (Short form) e.g. GMI for General Mechanical   Industries.
            • Date of Manufacturing (Month and Year).
            • Punch size in millimeter.
            • Any other Specifications/Special requirements like embossing, central break line,      beveled edge, chrome plating, groove on upper punches for rubber cups etc.
        • After receiving the consignment, punches and dies will be checked as per standard specification / sample punch set of respective punch set. Along with the following additional checks:-

Appearance (finishing of Punch set)

Damages (cracks/chips)

Height of punches (Working length)

Proper fitting of punches and dies on the machine

  • Record the observations in the  appropriate Annexure
    • Supplier should provide following documents with punch set :-

Drawing

Certificate of material of construction

Inspection report

  • ORDERING OF EXISTING PUNCH SET FROM SAME SUPPLIER:
    • Place the order to the manufacturer who had supplied earlier punch set   for the particular product.
    • Give one set to the manufacturer as a sample and repeat the step no. as above mentioned.
    • CHECKING OF PUNCHES AND DIES:
      • Each punch and die should be checked individually using the standard specification.
      • Check the details engraved on individual punch and die as above mentioned.  
      • For new punch set if supplier has provided all test documents then it should be taken for use after verification and QA approval based on in-house verification.
      • Checks for Punches:
        • Tip Dimension. Check individually UP and LP by vernier calliper.
        • Tip surface Check visually for scratches, damages, surface finish, cracks, pits, and spots and chrome plating (if applicable).
        • Body surface Check visually for scratches, damages, surface finish, cracks, pits, spot and chrome plating (if applicable)
        • Chamfer Check visually for angle, uniformity
        • Tips edge: Check visually for damages, cracks, sharpness and burr
        • Embossing

Check visually for letters, flattening of letters, burr, roughness, cracks and deep score.

  • Central Break Line

Check visually for position, flattening, roughness, cracks, deep score

  • Checks for Punches:Inner dimensions- Inner dimension of bore with help of vernier calliper and by inserting lower punch in it.   Inner surface, Check visually for scratches, damages, surface finish, cracks, pits, spots    and chrome plating (if applicable).Body surface, Check visually for surface finish, level uniformity, edges (both upper and lower surfaces)

NOTE: Check individual die by inserting upper and lower punch in it and check for its freeness

  • Frequency Of Checking The Punch SetWhen the punch set is new, Quality Assurance should certify the punch set. (Annexure V).   Visual checking of Punch set should be done after every batch and at the time of fixing or removing the punch set from machine.
    • PUNCH HEIGHT CHECKING:
      • Take the punch set from the punch set cabinet.
      • Clean all the upper and lower punches as per SOP and arrange them in sequence with the help of their serial numbers.
      • Assemble the punch height variation checking equipment.
      • Clean the platform of punch height checking equipment.
      • Place the Calibrated Standard Hobb (supplied along with equipment) on platform and adjust it below the dial knob.
      • Set dial indicator to ‘zero’ by rotating the dial of equipment. Recheck the ‘zero’ setting of dial indicator with standard Hob and check the height of punches as per following instructions.
      • Check the ‘Variation Working Length’ for deciding the suitability of the punch In all types of punches viz. Concave, Flat Beveled Edge etc.
      • Keep the punch in ‘Head DOWN and Tip UP’ position while checking the punch height i.e. Critical Working Length and find out the constant minimum reading on the dial by moving the tip-surface of punch against the pointer (actuator) of the dial gauge.
        • Check and record the variation in height of all punches in Annexure I Discard the punch if the difference is more than + 0.003 inch  (in case of round shaped) and +0.005 inch (in case of other than round shaped  than the standard height 133.600 mm).
        • Clean the platform and dismantle the equipment. Keep the equipment parts, dial and standard punch in the respective drawer.
        • Frequency of punch height checking is as per following table.
Punch set typePunch set lifeHeight-checking frequency
Circular4 million tabs/set2 million tabs/set
Other than circular2 million tabs/set1 million tabs/set
Double layered (circular)2 million tabs/set1 million tabs/set
Double layered (noncircular)1 million tabs/set0.5 million tabs/set

       1 set = 1 upper punch + 1 lower punch + 1 die

NOTE:

  • Punch height shall be checked as per height checking frequency or one year, whichever is earlier.
    • Always consider the minimum reading on the dial indicator, which shows the deepest point on the punch tip surface.
    • In case of embossed punch tip with break line the reading should be taken by adjusting the pointer on plain surface at the same location on each punch.
    • POLISHING OF PUNCHES AND DIES:
      • PUNCH SHOULD BE POLISHED WHEN.
        • There is burr or claw on punch tip.
        • Punch tip turns black.
        • Roughness on the tip is observed.
        • Sticking/picking problem is observed.
        • Appearance of tablet becomes dull.
      • DIE SHOULD BE POLISHED WHEN.
        • There is ring formation inside the die-bore.
        • Die-bore surface becomes black.
        • Corrosion is observed inside die-bore.
        • Wear or drag is observed in die-bore
      • POLISHING OF PUNCHES AND DIES.
Tooling typePolishing toolPolishing material
PunchesNylon brushesEmery paste
DiesFelt bobEmery paste
  • FREQUENCY OF POLISHING THE PUNCHES AND DIES:As and when required (Whenever the above problems are observed)Use the equipment for polishing of punches and dies and recommended polishing compounds as per SOP.
    • ISSUE AND RECEIPT OF PUNCHSETS:
      • ISSUING A PUNCH SET.
        • Depending on the product and the compression machine, select a punch set for issuing it to the required machine.
        • Take the punch set from Punch storage cabinet and clean the punches and dies as per SOP .
        • After cleaning, check:
          • Total number of punches and dies in the punch set.
          • Suitability for their use by checking the tip surface, body surface embossing etc. of the individual punch and die.
          • Issue the exact quantity of punches and dies for setting on the machine and store the spare/remaining punches and dies back into the respective drawer. Make the entry in punch Stock Card in  appropriate Annexure NO

Note: For uniform wear and tear of the Punches and Dies, use the tooling in rotation of 5 sets during product to product changeover or every week whichever is earlier.

E.g. For first time from 1 to 26 and next time from 6 to 31 and so on…. (Use every punch set in rotation).

  • RECEIVING A PUNCH SET FROM THE MACHINE.
    • After completion of the compression of a batch or the production plan, dismantle the punches and dies from the machine.
    • Clean the punches and dies as per SOP and check all the punches and dies individually and store them into the respective drawer of cabinet or the box by applying a thin smear of non-toxic food grade oil (as per Standards).
    • Record the number of punches and dies received in Punch Stock Card in appropriate Annexure
    • CLEANING OF PUNCHES AND DIES AND DUST CAPS:
      • CLEANING OF PUNCHES AND DIES :
        • Cleaning of the punch set shall be performed as per the SOP for cleaning of Punch & Dies
        • In case of campaign manufacturing, the punch and die set shall be cleaned after 5 batches or 3 days, whichever is earlier.
      • CLEANING OF DUST CAPS :
        • Carry the dust caps in a virgin polybag to the washing area.
        • Keep all the dust caps fully immersed in water for half hour. Scrub the dust caps, if required.
        • Clean with approx 2 kg of filtered potable water & finally rinse with purified water.
        • Dry the dust caps using filtered compressed air.
    • DISPOSAL OF PUNCH SETS:
      • Punch set to be disposed when whichever of the following is earlier.
        • Punch set should be disposed when the set becomes incomplete due to reduction in the number of upper punches/ lower punches or dies because of rejection during the usage of punch set.
        • A full set (upper punch/lower punch/die) should be disposed when it becomes unusable due to damage to the tip/head/body of the punch or die during handling and usage of the punch set or due to corrosion.
      • Procedure of disposal:
        • Collect all the defective upper punches/lower punches and dies along with incomplete punch sets, which are to be disposed..
        • Record the details of all these defective punches and dies and in Annexure III and prepare a ‘Scrap Transfer Note of all these punches and dies.
        • Deface the punches and dies with the help of grinder and transfer the punches and dies to the scrap yard and dispose them.
        • Disposal activity should be done only after approval by the Head- production/ Head – QA and Unit Head and by taking all the necessary safety precautions.
NOTE:
  • Punch trolley should be used to carry the punches and dies from storage area to compression area and back.
    • Punches should be stored in plastic sleeves.
    • Dial gauge and Standard Hobb should be calibrated at every year.
  • TRAINING:
    • As per SOP For Employee Training
  • DISTRIBUTION:
    • As per SOP ON SOP
  • ANNEXURE:

Annexure I   : Punch Height Checking Record.

Annexure II : Punch Stock Card

Annexure III  : Punches / Dies (Punch set) DestructionRecord.

Annexure IV : Standard Specification

Annexure V: Punch and Dies Certification

SOP for Preparation of 2.5% w/v Caustic soda solution

The purpose of this standard Operating Procedure (SOP) is to lay down a procedure for preparation of 2.5% w/v caustic soda solution.

This procedure is applicable for preparation of caustic soda solution used for cleaning of equipment and accessories in pellet section at manufacturing facility of Pharmaceutical   Industry.

  • PROCEDURE:
    • PREPARATION OF 2.5 % W/V CAUSTIC SODA SOLUTION:
      • Take the necessary acessoceries such as SS container, acid – alkali proof gloves and safety goggles.
      • Take 10 lt. Purified water in a clean SS container.
      • Take 250.00 Gms of Sodium Hydroxide pellets and add it into purified water slowly. Then mix this gently using SS spatula and keep it aside for five minutes for cooling.
      • Label the prepared solution properly.
      • After the completion of the operation destroy the remaining cleaning solution by diluting sufficiently and pouring into drain in washing area.
      • Use freshly prepared caustic soda solution only.
  • TRAINING:
  • As per SOP On Employee Training
  • ANNEXURE:

Annexure I    : Record of 2.5 % w/v Caustic Soda Solution Preparation and     Destruction of Unused Solution.

SOP For Job Responsibility

The purpose of this Standard Operating Procedure (SOP) is to lay down the procedure for defining job responsibilities of individuals.

  1. Objective :

The purpose of this Standard Operating Procedure (SOP) is to lay down the procedure for defining job responsibilities of individuals.

  • Scope :

This SOP is applicable to all responsible persons of pharmaceutical Industry       

  • Responsibility:

Officer QA – shall prepare the SOP co-ordination with all respective departments shall be responsible for Preparation of SOP.  

Executive QA / designee shall review the SOP,

Head Quality Assurance shall approve the SOP.

  • Procedure:

To maintain a satisfactory system of QA and manufacturing of drug product, as per cGMP requirement.

Each department shall be provided with defined responsibility to perform the task for manufacturing of the Drug Product to meet cGMP requirement.

The duties of each department are defined but not necessarily be limited to as follows.

Warehouse:

Preparation and review of the instruction for describing the receipt, identification, quarantine, storage and handling of raw materials/ Packing materials/ Finished product.

Receipt, identification, quarantine, storage and handling of material / product according to pre approved instructions.

Environmental monitoring of the area as per predefined procedures.

Making sure that any deviation is reported and investigated properly.

Making sure that storage area is cleaned.

Inventory control

Production

Preparing and reviewing the instructions for the production of products according to written procedures.

Producing products according to pre-approved instructions.

Reviewing all production batch records and ensuring that are completed and signed.

Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and conclusions are recorded.

Making sure those productions facilities are clean and disinfected when appropriate.

Making sure that the necessary calibrations are performed and recorded in respective areas.

Making sure that the premises and equipment are maintained and recorded in respective areas.

Making sure that validation protocols and reports are prepared and reviewed.

Evaluation of proposed changes in product, process or equipment.

Making sure that new and when appropriate, modified facilities and equipment are qualified.

Engineering

Preparation and review of the instruction for describing the procedure for preventive maintenance, breakdown maintenance.

Evaluating any change in equipment, machinery.

Calibration of equipment and instrument used in manufacturing.

Operation of all Utilities like Water, HVAC, Boiler, Compressed Air etc.

Execution of Installation and Operational Qualification of equipment as per approved protocol.

Quality Control

Sampling/testing and release of incoming, in process and finished product as per the laid down specifications and standard testing procedures.

Release / Reject of raw material / Packing Material/Finished Product.

Making sure that critical deviations are investigated and resolved.

Out of Specification Investigation.

Preparation and Standardization of volumetric solutions and reagents.

Inventory control of chemicals / Glassware / media etc.

Preparation and review of all SOP’s related to department, Specification and test procedures.

Initiation and review of any change related to the department.

Preparation and execution of validation protocol for method validation and Analyst validation.

Making sure that materials are appropriately tested and results are reported.

To conduct Stability Studies.

Calibration of instruments used in the Laboratories.

Handling of Reference standard and Working standard and qualification of working standard.

Quality Assurance

To ensure that Quality systems are maintained as per cGMP requirement.

Review of batch records and release of Finished Product.

Approval of all SOP’s, STP’s, Specifications and master processing records etc.

Making sure that all critical deviations are investigated and resolved.

To conduct Self Inspection and to conduct Vendor Evaluation.

Change Control review and Approval.

Review and Approval of all validation related activities.

Performing Product Quality review.

Handling and Investigation of Market Complaints and product recall.

Human Resource

To prepare procedure for personnel hygiene medical checkup, housekeeping.

Employee Welfare.

To coordinate for training to all employees.

To conduct regular medical checkups and house keeping

The department head shall ensure that adequate number of personnel with necessary qualification and experience are provided to complete the departmental responsibility. Department Head shall prepare job responsibility of every employee working in their department and shall explain the same to employee.

  • TRAINING:

As per Employee Training SOP

  • DISTRIBUTION:

         ANNEXURE:

Annexure-I                           :  Format for Job Responsibility

  • REFERENCES:

NiL

SOP on Procedure for the Operation of Fluidized Bed Dryer (FBD)

OBJECTIVE  :

The purpose of this SOP to describe the procedure for the operation of fluidized bed dryer (FBD).

SCOPE  :

This SOP is applicable for operation of fluidized bed dryer located in the tablet production department at Manufacturing site..

Equipment Name               :  Fluidized Bed Dryer.

Equipment ID No.               :

Manufactured by                 :

RESPONSIBILITY :

Production Officer/ Executive shall be responsible to supervise the operation of fluidized bed dryer.

IPQA Officer/ Executive shall be responsible for verifying the operation of fluidised bed dryer.

Head Production shall be responsible to check the procedure is followed as per SOP.

REFERENCES :

Nil

ABBREVIATIONS:

SOP        :   Standard operating procedure.

IPQA       :   In Process Quality Assurance.

FBD        :    Fluidized Bed Dryer.

I.D. No.  :     Identification Number 

DEFINITIONS :

Nil

GENERAL INSTRUCTIONS :

Check the cleanliness of fluidized bed dryer, its part and area.

Check the ‘CLEANED’ status label available on fluidized bed dryer.

Check the integrity of FBD bowl sieve and inspect the intactness of finger bag.

Check the proper fixing of finger bags, retarding chamber and bowl.

These FBD bags should be stored in separate bins and should be properly labeled.

Use dedicated FBD bag for each product and then check the proper fitting of FBD bag.

Check the steam filter before applying.

After charging powder in FBD bowl push the trolley in the dryer.

Check whether the earthling provided on the dryer are touching the FBD trolley.

Steam indicator valve to be checked during operation.

PROCEDURE :

Operation of Fluidized Bed Dryer:

Before starting the operation production officer / executive shall affix the activity status label having the details such as product name, B.No. Stage etc. to equipment and area and inform to IPQA officer / executive for line clearance.

Adjust the FBD bowl under the retarding chamber.

Switch ‘ON’ the mains.  Open the compressed air valve to apply pneumatic pressure 2.5 kg to 3.5 kg to lock the bowl.

While starting steam drying, Keep steam valve and by pass valve open initially to              drain the condensed water passing through the pipe. Close the condensed valve and adjust the steam valve so as to get the required air inlet temperature. Adjust the timer as per batch manufacturing record. 

Ensure that there is no leakage of air from FBD bowl and outlet.

Remove the container after shaking and rack the material. Again reset the product container and run for further drying. Take out the granules intermittently from the sampling points as and when required for checking the loss on drying.

After completion of operation shut ‘OFF’ the steam valve and air dry the material till the granules attains ambient temperature.

Shake the FBD bag and allow the material to settle down.

Release the compressed air pressure to unlock the FBD bowl from the retarding chamber. 

Remove the product container or go for the further process.

Affix “To be Cleaned “label to equipment .

Record the operation activity in equipment log sheet as per annexure – I.

Inspection of FBD bag shall be carried out for its integrity as per below given points

  1. Check bag for any small holes and torn.
  2. Check the finger of bag for stitches are intact.
  3. Check the corners of bag for intactness and stitches of corners .

Inspection of FBD bag shall be carried out for its integrity before and after the usage and record it in FBD bag usage record as per annexure –II.

After completion of operation clean the equipment as per cleaning procedure.

ANNEXURES:

Annexure – I   :  Equipment Log Sheet.

Annexure – II  :  FBD Bag Usage Record.

SOP For Preparation of Disinfectant Solution.

SOP For Preparation of Disinfectant Solution.

OBJECTIVE:

The purpose of this Standard Operating Procedure (SOP) is to lay down a procedure for the preparation and usage of disinfectant solutions.

SCOPE:

This procedure is applicable to agents used for disinfection at the manufacturing facility

RESPONSIBILITY:

Officer/ Executive shall be responsible for the preparation and Head of the production department shall be responsible for the usage of disinfectant solutions.

PROCEDURE:

PREPARATION OF 1% V/W (or as per Validation) 1st Disinfectant SOLUTION (For Degerming of Floors, walls, and furniture):

Take 9.90 kg (approx)(or as per Validation) purified water in S.S container. To it add 100 ml(or as per Validation) of  1st Disinfectant solution. Make final volume to 10 kg(or as per Validation) & mix the solution.

PREPARATION OF 1% V/W(or as per Validation) 2nd Disinfectant  SOLUTION (For Degerming of Floors, walls, and furniture):

Take 9.90 kg (approx) (or as per Validation) purified water in S.S container. To it add 100 ml(or as per Validation) of 2nd Disinfectant solution. Make final volume to 10 kg (or as per Validation) & mix the solution.

3rd  SOLUTION:

Preparation – Use this undiluted

Use–  For rapid hand and skin Antisepsis. Dispense sufficient quantity to wet the hands and fingernails. Rub vigorously until dry.

Precaution– Keep away from flame, source of heat and open electrical wires. Avoid direct contact with eyes and ears.

 NOTE:

  1. Change the proportion accordingly, if more or less quantity of solution is
  2. Always add disinfectant to water while making dilutions.
  3. Prepare the solution 15kg of sanitization solution for 7 drains in the production area.
  4. These solutions should be freshly prepared. The solution should be used within 24 hours from the time of preparation and must be destroyed by pouring it in to drain at the end of day operation by diluting with sufficient quantity of water.
  5. Use 1 % v/w 1st Disinfectant  Solution for first 15 days and 1 % v/w 2nd  Disinfectant Solution for remaining days of the month.
  6. Do not mix with other disinfectant or antiseptic solutions.
  7. Do not use the disinfectants after expiry.
  8. For composition, shelf life and other details of disinfectants refer SOP..

 

TRAINING:

Trainer: Head – Production/Designee

Trainees: Production Staff

DISTRIBUTION:

-as per Requirement

ANNEXURE:

Annexure-I:  Preparation And Usage of Disinfectant 1 % v/w 1st Disinfectant solution / 1% v/w 2nd Disinfectant  solution

Principles of Cleaning Validation

Principles of Cleaning Validation

  • Cleaning validation should be performed in order to confirm the effectiveness of
    any cleaning procedure for all product contact equipment. Simulating agents may
    be used with appropriate scientific justification. Where similar types of equipment are grouped together, a justification of the specific equipment selected for cleaning validation is expected.
  • A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation. It is not generally acceptable for this criterion alone to be used. Repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach.
  • It is recognised that a cleaning validation programme may take some time to complete and validation with verification after each batch may be required for some products, e.g. investigational medicinal products. There should be sufficient data from the verification to support a conclusion that the equipment is clean and available for further use.
  • Validation should consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities and equipment should be validated.
  • For all cleaning processes an assessment should be performed to determine the variable factors which influence cleaning effectiveness and performance, e.g. operators, the level of detail in procedures such as rinsing times etc. If variable factors have been identified, the worst case situations should be used as the basis for cleaning validation studies.
  • Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.
  • Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances.
  • If it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity. The risk presented by microbial and endotoxin contamination should be considered during the development of cleaning validation protocols.
  • The influence of the time between manufacture and cleaning and the time between cleaning and use should be taken into account to define dirty and clean hold times for the cleaning process.
  • Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the campaign should be considered and the maximum length of a campaign (in time and/or number of batches) should be the basis for cleaning validation exercises.
  • Where a worst case product approach is used as a cleaning validation model, a scientific rationale should be provided for the selection of the worst case product
    and the impact of new products to the site assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity and potency.
  • Cleaning validation protocols should specify or reference the locations to be sampled, the rationale for the selection of these locations and define the acceptance criteria.
  • Sampling should be carried out by swabbing and/or rinsing or by other means depending on the production equipment. The sampling materials and method should not influence the result. Recovery should be shown to be possible from all product contact materials sampled in the equipment with all the sampling methods used.
  • The cleaning procedure should be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated.
  • Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated equipment or other appropriate measures should be used for each product as indicated in chapters 3 and 5 of EudraLex, Volume 4, Part I.
  • Where manual cleaning of equipment is performed, it is especially important that the effectiveness of the manual process should be confirmed at a justified frequency.

Reference :-

Volume 4
EU Guidelines for
Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use
Annex 15: Qualification and Validation

What is Minimum Requirements of EU Agencies from Production section of Manufacturing site.?

Minimum Requirements in  Production section  for EU authorized Human Pharmaceutical products manufacturing site as per Eudralex Volume 4  part 1 Chapter 5: Production. 

 

Principle

Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorisations.

 

General

  • Production should be performed and supervised by competent people.
  • All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded.
  • All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labelled with the prescribed data.
  • Damage to containers and any other problem which might adversely affect the quality of a material should be investigated, recorded and reported to the Quality Control Department.
  • Incoming materials and finished products should be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution.
  • Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials.
  • All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation.
  • Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.
  • Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.
  • At every stage of processing, products and materials should be protected from microbial and other contamination.
  • When working with dry materials and products, special precautions should be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly active or sensitising materials.
  • At all times during processing, all materials, bulk containers, major items of equipment and where appropriate rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication should also mention the stage of production.
  • Labels applied to containers, equipment or premises should be clear, unambiguous and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (for example, quarantined, accepted, rejected, clean).
  • Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner.
  • Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by a competent person, with the involvement of the Quality Control department when appropriate.
  • Access to production premises should be restricted to authorised personnel.

 

Prevention of cross-contamination in production

 

  • Normally, the production of non-medicinal products should be avoided in areas and with equipment destined for the production of medicinal products but, where justified, could be allowed where the measures to prevent cross-contamination with medicinal products described below and in Chapter 3 can be applied. The production and/or storage of technical poisons, such as pesticides (except where these are used for manufacture of medicinal products) and herbicides, should not be allowed in areas used for the manufacture and / or storage of medicinal products.
  • Contamination of a starting material or of a product by another material or product should be prevented. This risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances, other starting materials, and products in process, from residues on equipment, and from operators’ clothing should be assessed. The significance of this risk varies with the nature of the contaminant and that of the product being contaminated. Products in which cross-contamination is likely to be most significant are those administered by injection and those given over a long time. However, contamination of all products poses a risk to patient safety dependent on the nature and extent of contamination.
  • Cross-contamination should be prevented by attention to design of the premises and equipment as described in Chapter 3. This should be supported by attention to process design and implementation of any relevant technical or organizational measures, including effective and reproducible cleaning processes to control risk of cross-contamination.
  • A Quality Risk Management process, which includes a potency and toxicological evaluation, should be used to assess and control the cross-contamination risks presented by the products manufactured. Factors including; facility/equipment design and use, personnel and material flow, microbiological controls, physico-chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from the evaluation of the products should also be taken into account. The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which premises and equipment should be dedicated to a particular product or product family. This may include dedicating specific product contact parts or dedication of the entire manufacturing facility. It may be acceptable to confine manufacturing activities to a
  • segregated, self contained production area within a multiproduct facility, where justified.
  • The outcome of the Quality Risk Management process should be the basis for determining the extent of technical and organisational measures required to control risks for cross-contamination. These could include, but are not limited to, the following:
  • Technical Measures
  1. Dedicated manufacturing facility (premises and equipment);
  2. Self-contained production areas having separate processing equipment and separate heating, ventilation and air-conditioning (HVAC) systems. It may also be desirable to isolate certain utilities from those used in other areas;
  3. Design of manufacturing process, premises and equipment to minimize opportunities for cross-contamination during processing, maintenance and cleaning;
  4. Use of “closed systems” for processing and material/product transfer between equipment;
  5. Use of physical barrier systems, including isolators, as containment measures;
  6. Controlled removal of dust close to source of the contaminant e.g. through localised extraction;
  7. Dedication of equipment, dedication of product contact parts or dedication of selected parts which are harder to clean (e.g. filters), dedication of maintenance tools;
  8. Use of single use disposable technologies;
  9. Use of equipment designed for ease of cleaning;
  10. Appropriate use of air-locks and pressure cascade to confine potential airborne contaminant within a specified area;
  11. Minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air;
  12. Use of automatic clean in place systems of validated effectiveness;
  13. For common general wash areas, separation of equipment washing, drying and storage areas.

 

  • Organisational Measures

  1. Dedicating the whole manufacturing facility or a self contained production area on a campaign basis (dedicated by separation in time) followed by a cleaning process of validated effectiveness;
  2. Keeping specific protective clothing inside areas where products with high risk of cross-contamination are processed;
  3. Cleaning verification after each product campaign should be considered as a detectability tool to support effectiveness of the Quality Risk Management approach for products deemed to present higher risk;
  4. Depending on the contamination risk, verification of cleaning of non product contact surfaces and monitoring of air within the manufacturing area and/or adjoining areas in order to demonstrate effectiveness of control measures against airborne contamination or contamination by mechanical transfer;
  5. Specific measures for waste handling, contaminated rinsing water and soiled gowning;
  6. Recording of spills, accidental events or deviations from procedures;
  7. Design of cleaning processes for premises and equipment such that the cleaning processes in themselves do not present a cross-contamination risk;
  8. Design of detailed records for cleaning processes to assure completion of cleaning in accordance with approved procedures and use of cleaning status labels on equipment and manufacturing areas;
  9. Use of common general wash areas on a campaign basis;
  10. Supervision of working behaviour to ensure training effectiveness and compliance with the relevant procedural controls.
  • Measures to prevent cross-contamination and their effectiveness should be reviewed periodically according to set procedures.

 

Validation

 

  • Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions should be recorded.
  • When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality.
  • Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process, should be validated.
  • Processes and procedures should undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results.

Starting materials

  • The selection, qualification, approval and maintenance of suppliers of starting materials, together with their purchase and acceptance, should be documented as part of the pharmaceutical quality system. The level of supervision should be proportionate to the risks posed by the individual materials, taking account of their source, manufacturing process, supply chain complexity and the final use to which the material is put in the medicinal product. The supporting evidence for each supplier / material approval should be maintained. Staff involved in these activities should have a current knowledge of the suppliers, the supply chain and the associated risks involved. Where possible, starting materials should be purchased directly from the manufacturer of the starting material.
  • The quality requirements established by the manufacturer for the starting materials should be discussed and agreed with the suppliers. Appropriate aspects of the production, testing and control, including handling, labelling, packaging and distribution requirements, complaints, recalls and rejection procedures should be documented in a formal quality agreement or specification.
  • For the approval and maintenance of suppliers of active substances and excipients, the following is required:
  • Active substances1

  • Supply chain traceability should be established and the associated risks, from active substance starting materials to the finished medicinal product, should be formally assessed and periodically verified. Appropriate measures should be put in place to reduce risks to the quality of the active substance.
  • The supply chain and traceability records for each active substance (including active substance starting materials) should be available and be retained by the EEA based manufacturer or importer of the medicinal product.
  • Audits should be carried out at the manufacturers and distributors of active substances to confirm that they comply with the relevant good manufacturing practice and good distribution practice requirements. The holder of the manufacturing authorisation shall verify such compliance either by himself or through an entity acting on his behalf under a contract. For veterinary medicinal products, audits should be conducted based on risk.
  • Audits should be of an appropriate duration and scope to ensure that a full and clear assessment of GMP is made; consideration should be given to potential cross- contamination from other materials on site. The report should fully reflect what was done and seen on the audit with any deficiencies clearly identified. Any required corrective and preventive actions should be implemented.
  • Further audits should be undertaken at intervals defined by the quality risk management process to ensure the maintenance of standards and continued use of the approved supply chain.
  • Excipients

  • Excipients and excipient suppliers should be controlled appropriately based on the results of a formalised quality risk assessment in accordance with the European Commission ‘Guidelines on the formalised risk assessment for ascertaining the appropriate Good Manufacturing Practice for excipients of medicinal products for human use’.
  • For each delivery of starting material the containers should be checked for integrity of package, including tamper evident seal where relevant, and for correspondence between the delivery note, the purchase order, the supplier’s labels and approved manufacturer and supplier information maintained by the medicinal product manufacturer. The receiving checks on each delivery should be documented
  • If one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing and release.
  • Starting materials in the storage area should be appropriately labelled (see section 13). Labels should bear at least the following information:
  1. The designated name of the product and the internal code reference where applicable;
  2. A batch number given at receipt;
  • Where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected);
  1. Where appropriate, an expiry date or a date beyond which retesting is necessary.

 

When fully computerised storage systems are used, all the above information need not necessarily be in a legible form on the label.

  • There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified (see Chapter 6).
  • Only starting materials which have been released by the Quality Control department and which are within their retest period should be used.
  • Manufacturers of finished products are responsible for any testing of starting materials2 as described in the marketing authorisation dossier. They can utilise partial or full test results from the approved starting material manufacturer but must, as a minimum, perform identification testing3 of each batch according to Annex 8.
  • The rationale for the outsourcing of this testing should be justified and documented and the following requirements should be fulfilled:
    1. Special attention should be paid to the distribution controls (transport, wholesaling, storage and delivery) in order to maintain the quality characteristics of the starting materials and to ensure that test results remain applicable to the delivered material;
    2. The medicinal product manufacturer should perform audits, either itself or via third parties, at appropriate intervals based on risk at the site(s) carrying out the testing (including sampling) of the starting materials in order to assure compliance with Good Manufacturing Practice and with the specifications and testing methods described in the marketing authorisation dossier;
  • The certificate of analysis provided by the starting material manufacturer/supplier should be signed by a designated person with appropriate qualifications and experience. The signature assures that each batch has been checked for compliance with the agreed product specification unless this assurance is provided separately;
  1. The medicinal product manufacturer should have appropriate experience in dealing with the starting material manufacturer (including experience via a supplier)
  2. including assessment of batches previously received and the history of compliance before reducing in-house testing. Any significant change in the manufacturing or testing processes should be considered;
  3. The medicinal product manufacturer should also perform (or via a separately approved contract laboratory) a full analysis at appropriate intervals based on risk and compare the results with the material manufacturer or supplier’s certificate of analysis in order to check the reliability of the latter. Should this testing identify any discrepancy then an investigation should be performed and appropriate measures taken. The acceptance of certificates of analysis from the material manufacturer or supplier should be discontinued until these measures are completed.
  • Starting materials should only be dispensed by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.
  • Each dispensed material and its weight or volume should be independently checked and the check recorded.
  • Materials dispensed for each batch should be kept together and conspicuously labelled as such.

 

Processing operations: intermediate and bulk products

  • Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation.
  • Intermediate and bulk products should be kept under appropriate conditions.
  • Critical processes should be validated (see “Validation” in this Chapter).
  • Any necessary in-process controls and environmental controls should be carried out and recorded.
  • Any significant deviation from the expected yield should be recorded and investigated.

 

Packaging materials

  • The selection, qualification, approval and maintenance of suppliers of primary and printed packaging materials shall be accorded attention similar to that given to starting materials.
  • Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorised access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by authorised personnel following an approved and documented procedure.
  • Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark.
  • Outdated or obsolete primary packaging material or printed packaging material should be destroyed and this disposal recorded.

 

Packaging operations

  • When setting up a programme for the packaging operations, particular attention should be given to minimising the risk of cross-contamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation.
  • Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list.
  • The name and batch number of the product being handled should be displayed at each packaging station or line.
  • All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity and conformity with the Packaging Instructions.
  • Containers for filling should be clean before filling. Attention should be given to avoid and remove any contaminants such as glass fragments and metal particles.
  • Normally, filling and sealing should be followed as quickly as possible by labelling. If it is not the case, appropriate procedures should be applied to ensure that no mix-ups or mislabelling can occur.
  • The correct performance of any printing operation (for example code numbers, expiry dates) to be done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand which should be re-checked at regular intervals.
  • Special care should be taken when using cut-labels and when over-printing is carried out off-line. Roll-feed labels are normally preferable to cut-labels, in helping to avoid mix-ups.
  • Checks should be made to ensure that any electronic code readers, label counters or similar devices are operating correctly.
  • Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing.
  • On-line control of the product during packaging should include at least checking the following:
  1. General appearance of the packages;
  2. Whether the packages are complete;
  • Whether the correct products and packaging materials are used;
  1. Whether any over-printing is correct;
  2. Correct functioning of line monitors.
  3. Samples taken away from the packaging line should not be returned.

 

  • Products which have been involved in an unusual event should only be reintroduced into the process after special inspection, investigation and approval by authorised personnel. Detailed record should be kept of this operation.
  • Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for before release.
  • Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure should be followed if un-coded printed materials are returned to stock.

 

Finished products

  • Finished products should be held in quarantine until their final release under conditions established by the manufacturer.
  • The evaluation of finished products and documentation which is necessary before release of product for sale is described in Chapter 6 (Quality Control).
  • After release, finished products should be stored as usable stock under conditions established by the manufacturer.

 

Rejected, recovered and returned materials

  • Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorised personnel.
  • The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. Record should be kept of the reprocessing.
  • The recovery of all or part of earlier batches which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture should be authorised beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded.
  • The need for additional testing of any finished product which has been reprocessed, or into which a recovered product has been incorporated, should be considered by the Quality Control Department.
  • Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; they may be considered for re-sale, re-labelling or recovery in a subsequent batch only after they have been critically assessed by the Quality Control Department in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for re-issue or re-use, although basic chemical reprocessing to recover active ingredient may be possible. Any action taken should be appropriately recorded.

 

Product shortage due to manufacturing constraints

  • The manufacturer should report to the marketing authorisation holder (MAH) any constraints in manufacturing operations which may result in abnormal restriction in the supply. This should be done in a timely manner to facilitate reporting of the restriction in supply by the MAH, to the relevant competent authorities, in accordance with its legal obligations4.

Reference :- 

“EudraLex
The Rules Governing Medicinal Products in the European Union
Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use
Part 1
Chapter 5: Production”